Over the past 7 years, several agents have been found to have clinical activity against HIV, and a number of other agents are in various stages of pre-clinical and early clinical development. However, the long-term activity of all the available agents is limited by incomplete activity, long-term toxicity, and the development of viral resistance. We are presently exploring whether the use of combinations of anti-HIV agents may address some or all of these limitations of therapy. Combinations of anti-HIV drugs can reduce toxicity, capitalize on drug synergy, delay the development of resistance, target various cells in the body, and target various organs. We have previously studied the combinations of AZT and acyclovir and an alternating regimen of AZT and ddC. We are now continuing a study of AZT with acyclovir alternating with ddI alternating with ddC. One central unresolved question is the relative advantages of giving alternating or simultaneous therapy with two (or more) agents. We have more recently started a study comparing a regimen of AZT alternating with ddI with one of AZT given simultaneously with ddI in patients with AIDS or symptomatic HIV infection who have not been heavily pre-treated. Preliminary results suggest that the CD4 rises are greater and more sustained with the simultaneous regimen. However, one of the principal advantages of alternating therapy is to reduce drug toxicity, and further study will be required to discern which is the better regimen.